Distinct Profiles of Myelin Distribution Along Single Axons of Pyramidal Neurons in the Neocortex

Tomassy, Giulio Srubek; Berger, Daniel R.; Chen, Hsu-Hsin; Kasthuri, Narayanan; Hayworth, Kenneth J.; Vercelli, Alessandro; Seung, H. Sebastian; Lichtman, Jeff W.; Arlotta, Paola

doi:10.1126/science.1249766

Cited by 498 publications

(541 citation statements)

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“…E14.5 corresponds to a stage when key brain developmental events are taking place; neurogenesis already has reached its peak in both the nascent diencephalon and the telencephalon (2,18,19). Conversely, by 7-8 weeks of age, all major postnatal developmental milestones have been achieved, including myelination, and the mouse brain can be considered mature (20,21).…”

Section: Resultsmentioning

confidence: 99%

Spatiotemporal expression and transcriptional perturbations by long noncoding RNAs in the mouse brain

Goff

Groff

Sauvageau

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

159

131

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Long noncoding RNAs (lncRNAs) have been implicated in numerous cellular processes including brain development. However, the in vivo expression dynamics and molecular pathways regulated by these loci are not well understood. Here, we leveraged a cohort of 13 lncRNAnull mutant mouse models to investigate the spatiotemporal expression of lncRNAs in the developing and adult brain and the transcriptome alterations resulting from the loss of these lncRNA loci. We show that several lncRNAs are differentially expressed both in time and space, with some presenting highly restricted expression in only selected brain regions. We further demonstrate altered regulation of genes for a large variety of cellular pathways and processes upon deletion of the lncRNA loci. Finally, we found that 4 of the 13 lncRNAs significantly affect the expression of several neighboring proteincoding genes in a cis-like manner. By providing insight into the endogenous expression patterns and the transcriptional perturbations caused by deletion of the lncRNA locus in the developing and postnatal mammalian brain, these data provide a resource to facilitate future examination of the specific functional relevance of these genes in neural development, brain function, and disease.T he exquisite complexity of the mammalian brain derives from its vast diversity of neuronal and glial cell types (1, 2). The specification and differentiation of such a variety of cell types during brain development is finely orchestrated spatiotemporally by the regulation of complex transcriptional programs. Increasing evidence points to a role for long noncoding RNAs (lncRNAs) as key regulatory elements of this process. Intriguingly, within the mammalian body, the largest repertoire and diversity of lncRNA genes outside the germ line occurs in the brain (3-10), where lncRNAs exhibit regional and cell-specific localization (6, 10). Although many unanswered questions remain regarding the functional activity and molecular mechanisms of lncRNA loci, the expression patterns of lncRNAs may serve as a proxy signal for important, context-specific biological activity.A role for lncRNA genes in brain development and function is supported by the fact that ablation of two lncRNA loci, Evf2 and Pantr2 (linc-Brn1b), perturbs neuronal development (11, 12). Loss of Evf2, a developmentally regulated lncRNA that controls transcriptional activity through cooperation with the homeodomain protein DLX-2 (11), leads to abnormal development and synaptic function of hippocampal GABAergic interneurons (11). Similarly, ablation of the Pantr2 locus results in a decreased number of intermediate progenitors in the developing telencephalon, reduced neurons in L2/3 of the cerebral cortex, and disorganization of the barrel cortex (12). Furthermore, human genetic studies have pointed to lncRNAs as potential factors in brain disorders (10,(13)(14)(15)(16).To gain preliminary insights into the functional and physiological relevance of lncRNA loci in vivo, we previously generated knockout (KO) mouse models of ...

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Section: Resultsmentioning

confidence: 99%

Spatiotemporal expression and transcriptional perturbations by long noncoding RNAs in the mouse brain

Goff

Groff

Sauvageau

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

159

131

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“…This prediction would be compatible with the idea, dating back to Flechsig (2), that association cortical areas are the focus of a relatively late wave of myelinogenesis. The intracortical location of strongest maturational changes in MT, corresponding approximately to the boundary between layers V (internal pyramid) and VI, further suggests that adolescent intracortical myelination may be concentrated on the proximal segments of efferent projections from pyramidal neurons (20).…”

Section: Discussionmentioning

confidence: 99%

“…level, this signal likely reflects a developmentally late myelination of efferent axonal segments immediately distal to the axonal hillock of pyramidal cells (20). MRI sequences have been recently developed for myelin mapping in humans (21).…”

Section: Significancementioning

confidence: 99%

Adolescence is associated with genomically patterned consolidation of the hubs of the human brain connectome

Whitaker

Vértes

Romero-García

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

505

534

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How does human brain structure mature during adolescence? We used MRI to measure cortical thickness and intracortical myelination in 297 population volunteers aged 14-24 y old. We found and replicated that association cortical areas were thicker and less myelinated than primary cortical areas at 14 y. However, association cortex had faster rates of shrinkage and myelination over the course of adolescence. Age-related increases in cortical myelination were maximized approximately at the internal layer of projection neurons. Adolescent cortical myelination and shrinkage were coupled and specifically associated with a dorsoventrally patterned gene expression profile enriched for synaptic, oligodendroglial-and schizophrenia-related genes. Topologically efficient and biologically expensive hubs of the brain anatomical network had greater rates of shrinkage/myelination and were associated with overexpression of the same transcriptional profile as cortical consolidation. We conclude that normative human brain maturation involves a genetically patterned process of consolidating anatomical network hubs. We argue that developmental variation of this consolidation process may be relevant both to normal cognitive and behavioral changes and the high incidence of schizophrenia during human brain adolescence. A dolescence is associated with major behavioral, social, and sexual changes as well as increased risk for many psychiatric disorders (1). However, human brain maturation during adolescence is not yet so well understood. Historically, pioneering studies used histological techniques to show that distinct areas of cortex were differentially myelinated in postmortem examination of perinatal tissue, suggesting "myelinogenesis" as an important process in human brain development (2, 3). MRI can measure human brain development more comprehensively and over a wider age range than is possible for postmortem anatomists. The thickness of human cortex can be reliably and replicably measured by MRI (4), and longitudinal studies have shown that cortical thickness (CT; millimeters) monotonically shrinks over the course of postnatal development, with variable shrinkage rates estimated for different age ranges (5-11; review in ref. 12). CT typically shrinks from about 3.5 mm at age 13 y old (9) to about 2.2 mm at age 75 y old (10, 11). Rates of cortical shrinkage are faster during adolescence (approximately −0.05 mm/y) than in later adulthood or earlier childhood (9).What does this MRI phenomenon of cortical shrinkage represent at a cellular level? There are broadly two tenable models: pruning and myelination. Basic physical principles of MRI predict that shorter longitudinal (T1) relaxation times reflect either a reduction in the fraction of "watery" cytoplasmic material, like cell bodies, synapses, or extracellular fluid, or an increase in the fraction of "fatty" myelinated material, like axons. Pruning models propose that cortical shrinkage in adolescence represents loss or remodeling of synapses, dendrites, or cell bodies (13). Myelin...

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“…Such vision would also explain why increasing the number of the wraps 98 results in an increase in CAP speed: the thicker the sheath the more ATP is produced. A study of 99 myelin distribution along single axons showed that neocortical pyramidal in the murine brain 100 neurons comprise unmyelinated tracts, longer than previously thought (Tomassy et al, 2014).…”

mentioning

confidence: 90%

“…The classical theory assuming that the voltage gated channels are "set aside" when 109 the nerve is being wrapped from the sheath, gathering into the Ranvier Nodes, is put into serious 110 doubt in light of recent findings (Tomassy et al, 2014 Figure -Simplified picture: in an unmyelinated axonal trait the speed of the Compound Axon Potential (CAP) is low because the supply of ATP is relatively slow. In a myelinated axonal trait the speed of CAP progressively increase thanks to the ATP supply by myelin, so that the correct polarization is quickly restored.…”

mentioning

confidence: 99%

Myelin can't change the basic mechanisms of axonal conduction

Morelli

Panfoli

2017

Preprint

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14Starting from recent literature data, we propose a novel interpretation of nerve conduction 15 mechanism in myelinated nerves. A new hypothesis is proposed, tending to bridge the theoretical 16 gap existing to date between the basic physical-chemical mechanism of nerve conduction and its 17 adaptation to myelination. The considerations exposed imply a unification of the nerve conduction 18 mechanism, also identifying a precise role for myelin: an ATP-supplying energetic role.

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Distinct Profiles of Myelin Distribution Along Single Axons of Pyramidal Neurons in the Neocortex

Cited by 498 publications

References 38 publications

Spatiotemporal expression and transcriptional perturbations by long noncoding RNAs in the mouse brain

Spatiotemporal expression and transcriptional perturbations by long noncoding RNAs in the mouse brain

Adolescence is associated with genomically patterned consolidation of the hubs of the human brain connectome

Myelin can't change the basic mechanisms of axonal conduction

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